The overarching goal of R01 renewal is to continue our work on a multisystem degenerative disorder with muscle weakness and fronto-temporal dementia. VCP pathologies are unified by ubiquitin and TDP43 inclusions. VCP disease mutations affect multiple cellular process such as autophagy and endolysosomal trafficking that converge at the lysosome. Recently we have identified a critical role for VCP in maintaining lysosome integrity that is impaired in the setting of disease mutatins. We plan to perform the following aims will 1) Evaluate the role of VCP in lysophagy in neurons and muscle; 2) Evaluate lysosome mediated signaling pathways such as mTORC1 and TFEB in the brains of mice with VCP disease mutations; 3) Explore the role of VCP in the endolysosomal escape of proteopathic seeds. Upon completion we will understand the role of VCP in lysosomal homeostasis and how this is affected by VCP disease mutations in muscle and neurons.